1. Field of the Invention
The present invention relates generally to the fields of biology and medicine. The present invention is directed to methods and compositions useful in increasing in mammals the absorption and retention of polypeptides. More particularly, the invention is directed to lipid-conjugated interferon having increased liver uptake and increased plasma half-life.
2. Background Art
Interferon-α (IFN-α) is considered the most effective antiviral agent for chronic viral hepatitis that currently affects approximately 800 million people worldwide (Hoofnagle et al., N. Engl. J. Med. 336:347 (1997)). However, the short half-life and lack of liver-specific affinity hamper the IFN-α response. A sustained response is achieved in only one-third of patients with chronic hepatitis B and in only one-fifth of patients with chronic hepatitis C (Davis et al., N. Engl. J. Med. 321:1501 (1989); Poynard et al., Hepatology 24:778 (1996)).
Pegylation is most commonly used to modify IFN-α. Pegylated IFN-α, e.g., PEG-INTRON, was thus developed to prolong its half-life. Nevertheless, pegylation results in a heterogeneous species (Wang et al., Adv. Drug Delivery Rev. 54:547 (2002)). For PEG-INTRON, a nonselective, succinimidyl carbonate chemistry was used and consequently produced a mixture of pegylated forms: polyethylene glycol (PEG) with an average molecular weight of 12,000 Daltons is attached to the amine groups of at least 14 amino acid residues of IFN-α by covalent linkages (Wang et al., Biochemistry 39:10634 (2000)). Although the serum half-life was increased in pegylated IFNs with increased molecular weights of PEGs, the in vitro potency was significantly reduced by more than 75%. The increased hydrophilicity and bulkiness accordingly reduces the affinity of IFN-α for the liver.